neurobiology of nicotine addiction
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Neurobiology of Nicotine
Addiction
David McFadden, MD, MPH
Mayo Clinic Nicotine DependenceCenter
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Frustration
Patient viewpoint--ambivalence
90% know cigarette smoking is harmful and
want to quit.
Most smokers feel guilty and feel they have
let themselves, their spouse, family and care
provider down.
But most smokers are reluctant to quit andmake only brief attempts to quit and often
experience relapse if they do quit.
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Frustration
Health Care Provider viewpoint
Failure to help patient quit smoking may
weaken care providers resolve to try again
Tendency to blame the patient for non
compliance
Failure to understand the addictive physiology
and consequences of nicotine addiction whichpromotes relapse
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Psychoactive Substance
DependenceDSM_IV
Three or more of the following: Tolerance
Substance taken in larger amounts or over alonger period than intended
Persistent desire or unsuccessful efforts to cut
down or control use
Great deal of time spent in activities necessary to
obtain or use the substance or recover from its
effects
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Dependence diagnosis criteria
(continued) Important social, occupational, or recreationalactivities given up or reduced because of use
Continued use despite knowledge of having
had persistent or recurrent problems caused by
the substance
Withdrawal symptoms when attempt to
discontinue
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Cigarette smoking-not a habit
Habits=automatic routine, repeated
regularly and without thinking
Addictions are compulsions characterized
by subjective distress when routine
behaviors are forbidden.
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Nicotine hard-wired
Nicotine creates a motivation for the
target behavior (smoking) that is
rendered undeniable by the abnormal
amplified negative emotionalconsequences of unresolved compulsion.
This association becomes hard-wired
and persists over time
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Addictionalternative view
Continued smoking could no longer be
considered a manifestation of motivation
deficit, but instead must be considered a
disorder of an abnormally amplifiedmotivation NOT to quit
Cessation treatment should focus less on
the consequences of tobacco use andmore on the amplified motivations NOT to
quit
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Nicotine absorption
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There seems no doubt that the kick of acigarette is due to the concentration of nicotine
in the blood-streamand this is a product of thequantity of nicotine in the smoke and the speedof transfer of that nicotine from the smoke to theblood-stream.
Nicotine is in the smoke in two forms as freenicotine base (think of ammonia) and as anicotine salt (think of ammonium chloride) andit is almost certain that the free nicotine base isabsorbed faster into the blood-stream.
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o p
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Cigarette-efficient nicotine
delivery device Capable of producing very rapid peaks in
the arterial concentration of nicotine
Nicotine absorbed in alveoli of lung and
circulates via pulmonary veins to Left
heart. (bypasses the right heart)
Nicotine circulates to brain within 7-10
seconds where nicotine receptors
stimulate dopamine release
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Cigarettes and Tobacco
Dependence
Cigarette is the most efficient delivery device for
nicotine that exists- better than intravenous
Cigarette manufacturers have modified cigarettes
over the past decades to maximize nicotine delivery
to the brain
High doses of arterial nicotine cause upregulation of
the nicotinic acetylcholine receptors
Genetic factors influence tobacco dependence
Left untreated 60% of smokers die from a tobacco-
caused disease
Hurt RD, Robertson CR JAMA 280:1173, 1998 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
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The cigarette should be conceived not as aproduct but as a package. The product is nicotine.
Think of the cigarette pack as a storage containerfor a days supply of nicotine:
Think of the cigarette as a dispenser for a dose
unit of nicotine:
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Low Tar Low Nicotine CigarettesFTC Method
Determines relative yield of individual cigarettesby smoking them in a smoking machine
Machine draws 35ml puff of 2 seconds duration
every minute
Cigarette smoked down to 23mm butt length
Cambridge filter collects the particulate matter
Does not measure the gas phase free nicotine
2008 no longer used and as of June 2010 no
longer can use light terminology
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Low Tar Low Nicotine CigarettesVentilation
Ventilation holes one of key technologies to
manipulate tar and nicotine yields
Electrostatic or laser perforations of the filter or
paper
Ventilation holes in most brands are not visible
2/3s of U.S. smokers are unaware of ventilation
holes or that blocking then increases tar/nicotineyield
Many smokers block (consciously or not) the
ventilation holes with their lips on fingers 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
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arcinogens Excreted by Smokers o
Regular or Light Cigarettes 150 smokers of regular or light
cigarettes
Nicotine metabolites-Serum cotinine and
urine NNAL, NNAL-Gluc, and 4aminobiphenyl hemoglobin adductsmeasured
Essentially the same concentrations ofwere present in light as in regularcigarette smokers.
Bernert J.T., et. al. Nic & Tob Res 7:729, 2005 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
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Nicotine effect on the brain
Brain imaging studies show nicotine
acutely increases activity in the prefrontal
cortex, thalamus and visual system brain
circuits
There is stimulation of central
acetylcholine receptors (nAChRs) which
results in release of severalneurotransmitters most important -
Dopamine 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
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Mesolimbic system
Ventral Tegmental area (VTA)-collection of
nerve cells located midline on the floor of
the midbrain
Neurons of the VTA send projections to
target the Nucleus Accumbens in the
prefrontal region of the brain
The Nucleus Accumbensreward center
for most drugs of abuse
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Central Nervous System
Reward Center
Dopamine (DA) release in the nucleus accumbens is thought to be
the final common pathway for the rewarding effects of most drugs
of abuse 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
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Mesolimbic system
VTA contains dopaminergic neurons that
respond to external rewarding stimuli such
as food, sex and social interaction as well
as aversive stimuli and stress.
VTA stimulation promotes a generalized
behavioral arousal under both positive and
negative stimuli.
seeking of safety
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Neurophysiology of nicotine
VTAs inputs are transmitted by cholinergic
pathways and receptors.
Nicotine hijacks these receptors and
compels them to produce dopamine,
creating a powerful but artificial safety
signal.
Most potent drugmore potent than
cocaine, amphetamine and morphine to
compel repetitive behavior 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
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Different types of nAChr
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Nicotine addiction-animal study
Powerful motivator of behavior
Animal studies
Prolonged foot shock behavior extinction
Lever pressing of nicotine exposed monkeys
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Nicotine Stimulates Release of
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NICOTINE
DOPAMINE Pleasure, Appetite Suppression
NOREPINEPHRINE Arousal, Appetite Suppression
ACETYLCHOLINE Arousal, Cognitive Enhancement
GLUTAMATE Learning, Memory Enhancement
SEROTONIN Mood Modulation,
Appetite Suppression
BETA-ENDORPHIN Reduction of Anxiety and Tension
GABA Reduction of Anxiety and Tension
Nicotine Stimulates Release of
Many Different Neurotransmitters
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Nicotine actions
Induces stimulation and pleasure
Reduces stress/anxiety
Improves concentration, reaction time andtask performance
Prevents withdrawal symptoms by keeping
nAChRs in desensitized state
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Smoking Saturates Nicotinic
Receptors Radioligand allows for visualization
of 42 nAChRs
Position Emission Tomography
(PET) Scans 11 smokers had 14 PET scan
sessions
Smoked: none, 1 puff, 3 puffs, 1cigarette or 2-3 cigarettes (satiety)
Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
mo ng a ura es co n c
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mo ng a ura es co n cReceptors
Results 1-2 puffs of a cigarette 50%occupancy of 42 nAChRs for 3 hours
after smoking
One cigarette 88% receptor
occupancy and cigarette craving
Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006
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Smoking Saturates Nicotinic
Receptors
Brody, A.L. Arch Gen Psychiatry. 63;907-915, 2006
0.0 Cigarette 0.1 Cigarette 0.3 Cigarette 1.0 Cigarette 3.0 Cigarette
kBq/mL
9
0
Nondisplaceable
MRI
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Neuroadaptation
Repetitive Nicotine exposure
Upregulation -Increase in nAChRs
Response to nicotine-mediated
desensitization of receptors which may lead totolerance/dependence
Daily smoking maintains near-complete
saturation and desensitization of nAChRsAvoids withdrawal
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Conditioning
environmental factors (cues) contribute to
urge to smoke (after meals, with coffee,
with friends)
Cue often is to avoid irritability
Association between cues and anticipated
drug effect drives urge
May maintain nicotine use while nAChRs
are desensitized
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Nicotine Addiction
Physical DependencePsychological Dependence:
Conditioned Response to Cues
The Five Senses Emotions (positive and negative)
Cues trigger neurotransmitter release
Anticipation of Nicotinic receptor activation and
Dopamine release
Craving/Urges
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Withdrawal Syndrome or"Abstinence Syndrome"
Pathophysiologic disturbances
which result when a drug to
which an organism is physicallydependent is stopped.
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Craving
An intense desire to fulfill an unsatisfiedstate
As opposed to like
Positively correlated with relapse in twoways
Intensity during early quit
Momentary craving associated with immediaterelapse long after initial quit
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The experience:
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The experience:
Withdrawal Symptoms
Insomnia
Restlessness
Anxiety, Irritability,
Frustration, Anger Difficulty concentrating
Sad, depressed mood,
anhedonia
Increased appetite
Decreased heart rate
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Oth C
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Other Common
Withdrawal Symptoms
Headache
Mouth ulcers
Nausea
Constipation
Diarrhea
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Timeline of Nicotine WithdrawalFor most smokers, withdrawal symptoms
last for a few weeks and then resolve.
Cravings can be frequent and intense early,
but become less intense and less frequent
over timeStop Date
In
tensity
Time 2012 MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. ALL RIGHTS RESERVED
e ca on:
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e ca on:Effects on Withdrawal &
Urges
Stop Date
Intensity
Without Medication
With Medication
Time
Intensity
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High Relapse
Most people who smoke want to stop
80% of smokers who try to quit on their own
relapse within 1 month Only 3% remain abstinent at 6 months
Nicotine addiction=chronic disease
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Dealing with frustration
Patients internal conflictambivilance
Our responsibility is to help patients
resolve ambivalence
Motivational interviewing which enhances
motivation to change through reflective
listening without confrontation or judging
Ellicit trust by demonstrating Empathy-develop a sense of shared experience
Joiningdevelop shared goals
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Dealing with Frustration
Validationconfirm that the patients
experience/frustration with quitting has a
biologic/physiologic basis, but dont
undermine self-efficacy by overemphasizing how difficult quitting can be
Hope-hopelessness is a common barrier
to behavior change in addiction.
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Dealing with frustration
HopeWork to reinvigorate hope by
maintaining a positive non judgmental
attitude, emphasizing creative solutions to
common problems.
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Not a Bad Person with a Bad Habit, but a
Good Person with a Difficult Disease--Tom Gauvin, NDC Counselor
It Is A Disease
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References
1. Neurobiology of Nicotine Addiction:
Implications for smoking cessation
Treatment Neal L Benowitz, MD
American Journal of Medicine (supplement)vol. 121 (4A) S3-S10
April, 2008
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References
2. Leone, FT et el; Developing a Rational
Approach to Tobacco use Treatment in
Pulmonary Practice: A review of the
Biological Basis of Nicotine Addiction;Clinical Pulmonary Medicine,
Vol 19, No. 2, March, 2012
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Association for the Treatment of
Tobacco Use and Dependence
An organization of providers
dedicated to the promotion of andincreased access to evidence-based
tobacco treatment for the tobacco user.
www.attud.org
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